bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024–11–10
eightteen papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
  2. Mitochondrial elongation impairs breast cancer metastasis.
  3. Alveolar and Bone Marrow-derived Macrophages Differ in Metabolism and Glutamine Utilization.
  4. A diet-dependent host metabolite shapes the gut microbiota to protect from autoimmunity.
  5. GPR56: GPCR as a guardian against ferroptosis.
  6. Quantifying acyl-chain diversity in isobaric compound lipids containing monomethyl branched-chain fatty acids.
  7. PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity.
  8. CLSTN3B promotes lipid droplet maturation and lipid storage in mouse adipocytes.
  9. Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade.
  10. Protocol for studying macrophage lipid crosstalk with murine tumor cells.
  11. Glutamine modulates neutrophil recruitment and effector functions during sterile inflammation.
  12. PHGDH Induction by MAPK is Essential for Melanoma Formation and Creates an Actionable Metabolic Vulnerability.
  13. Metabolite signatures of chronological age, aging, survival, and longevity.
  14. Blockade of TREM2 ameliorates pulmonary inflammation and fibrosis by modulating sphingolipid metabolism.
  15. Neuroprotective effect of neuron-specific deletion of the C16 ceramide synthetic enzymes in an animal model of multiple sclerosis.
  16. Does a transmembrane sodium gradient control membrane potential in mammalian mitochondria?
  17. The dithiol mechanism of class I glutaredoxins promotes specificity for glutathione as a reducing agent.
  18. Piezo1 restrains proinflammatory response but is essential in T cell-mediated immunopathology.
  1. Nature. 2024 Nov 06.
    Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
    Keun Woo Ryu, Tak Shun Fung, Daphne C Baker, Michelle Saoi, Jinsung Park, Christopher A Febres-Aldana, Rania G Aly, Ruobing Cui, Anurag Sharma, Yi Fu, Olivia L Jones, Xin Cai, H Amalia Pasolli, Justin R Cross, Charles M Rudin, Craig B Thompson.
      Mitochondria serve a crucial role in cell growth and proliferation by supporting both ATP synthesis and the production of macromolecular precursors. Whereas oxidative phosphorylation (OXPHOS) depends mainly on the oxidation of intermediates from the tricarboxylic acid cycle, the mitochondrial production of proline and ornithine relies on reductive synthesis1. How these competing metabolic pathways take place in the same organelle is not clear. Here we show that when cellular dependence on OXPHOS increases, pyrroline-5-carboxylate synthase (P5CS)-the rate-limiting enzyme in the reductive synthesis of proline and ornithine-becomes sequestered in a subset of mitochondria that lack cristae and ATP synthase. This sequestration is driven by both the intrinsic ability of P5CS to form filaments and the mitochondrial fusion and fission cycle. Disruption of mitochondrial dynamics, by impeding mitofusin-mediated fusion or dynamin-like-protein-1-mediated fission, impairs the separation of P5CS-containing mitochondria from mitochondria that are enriched in cristae and ATP synthase. Failure to segregate these metabolic pathways through mitochondrial fusion and fission results in cells either sacrificing the capacity for OXPHOS while sustaining the reductive synthesis of proline, or foregoing proline synthesis while preserving adaptive OXPHOS. These findings provide evidence of the key role of mitochondrial fission and fusion in maintaining both oxidative and reductive biosyntheses in response to changing nutrient availability and bioenergetic demand.
    DOI:  https://doi.org/10.1038/s41586-024-08146-w
  2. Sci Adv. 2024 Nov 08. 10(45): eadm8212
    Mitochondrial elongation impairs breast cancer metastasis.
    Lucía Minarrieta, Matthew G Annis, Yannick Audet-Delage, Hellen Kuasne, Alain Pacis, Catherine St-Louis, Alexander Nowakowski, Marco Biondini, Mireille Khacho, Morag Park, Peter M Siegel, Julie St-Pierre.
      Mitochondrial dynamics orchestrate many essential cellular functions, including metabolism, which is instrumental in promoting cancer growth and metastatic progression. However, how mitochondrial dynamics influences metastatic progression remains poorly understood. Here, we show that breast cancer cells with low metastatic potential exhibit a more fused mitochondrial network compared to highly metastatic cells. To study the impact of mitochondrial dynamics on metastasis, we promoted mitochondrial elongation in metastatic breast cancer cells by individual genetic deletion of three key regulators of mitochondrial fission (Drp1, Fis1, Mff) or by pharmacological intervention with leflunomide. Omics analyses revealed that mitochondrial elongation causes substantial alterations in metabolic pathways and processes related to cell adhesion. In vivo, enhanced mitochondrial elongation by loss of mitochondrial fission mediators or treatment with leflunomide notably reduced metastasis formation. Furthermore, the transcriptomic signature associated with elongated mitochondria correlated with improved clinical outcome in patients with breast cancer. Overall, our findings highlight mitochondrial dynamics as a potential therapeutic target in breast cancer.
    DOI:  https://doi.org/10.1126/sciadv.adm8212
  3. Am J Respir Cell Mol Biol. 2024 Nov 05.
    Alveolar and Bone Marrow-derived Macrophages Differ in Metabolism and Glutamine Utilization.
    Christine L Vigeland, Jordan D Link, Henry S Beggs, Yazan Alwarawrah, Brandie M Ehrmann, Hong Dang, Claire M Doerschuk.
      Changes in metabolic activity are key regulators of macrophage activity. Pro-inflammatory macrophages upregulate glycolysis, which promotes an inflammatory phenotype, whereas pro-repair macrophages rely upon oxidative metabolism and glutaminolysis to support their activity. Work to understand how metabolism regulates macrophage phenotype has been done primarily in macrophage cell lines and bone marrow-derived macrophages (BMDM). Our study sought to understand changes in metabolic activity of murine tissue-resident alveolar macrophages (AM) in response to LPS stimulation and to contrast them to BMDM. These studies also determined the contribution of glutamine metabolism using the glutamine inhibitor, DON. We found that compared to BMDM, AM have higher rates of oxygen consumption and contain a higher concentration of intracellular metabolites involved in fatty acid oxidation. In response to LPS, BMDM but not AM increased rates of glycolysis. Inhibition of glutamine metabolism using DON altered the metabolic activity of AM but not BMDM. Within AM, glutamine inhibition led to increases in intracellular metabolites involved in glycolysis, the TCA cycle, fatty acid oxidation, and amino acid metabolism. Glutamine inhibition also altered the metabolic response to LPS within AM but not BMDM. Our data reveal striking differences in the metabolic activity of AM and BMDM.
    Keywords:  glutamine; glycolysis; lipids; macrophage; metabolomics
    DOI:  https://doi.org/10.1165/rcmb.2023-0249OC
  4. Cell Rep. 2024 Oct 18. pii: S2211-1247(24)01242-7. [Epub ahead of print] 114891
    A diet-dependent host metabolite shapes the gut microbiota to protect from autoimmunity.
    Margaret Alexander, Vaibhav Upadhyay, Rachel Rock, Lorenzo Ramirez, Kai Trepka, Patrycja Puchalska, Diego Orellana, Qi Yan Ang, Caroline Whitty, Jessie A Turnbaugh, Yuan Tian, Darren Dumlao, Renuka Nayak, Andrew Patterson, John C Newman, Peter A Crawford, Peter J Turnbaugh.
      Diet can protect from autoimmune disease; however, whether diet acts via the host and/or microbiome remains unclear. Here, we use a ketogenic diet (KD) as a model to dissect these complex interactions. A KD rescued the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis in a microbiota-dependent fashion. Dietary supplementation with a single KD-dependent host metabolite (β-hydroxybutyrate [βHB]) rescued EAE, whereas transgenic mice unable to produce βHB in the intestine developed more severe disease. Transplantation of the βHB-shaped gut microbiota was protective. Lactobacillus sequence variants were associated with decreased T helper 17 cell activation in vitro. Finally, we isolated an L. murinus strain that protected from EAE, which was phenocopied by a Lactobacillus metabolite enriched by βHB supplementation, indole lactate. Thus, diet alters the immunomodulatory potential of the gut microbiota by shifting host metabolism, emphasizing the utility of taking a more integrative approach to study diet-host-microbiome interactions.
    Keywords:  CP: Immunology; CP: Microbiology; autoimmune disease; gut microbiome; immune activation; ketogenesis; ketogenic diet; lactobacillus; multiple sclerosis; neuroinflammation; nutrition; trytophan metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.114891
  5. Cell Metab. 2024 Nov 05. pii: S1550-4131(24)00363-2. [Epub ahead of print]36(11): 2355-2356
    GPR56: GPCR as a guardian against ferroptosis.
    Yuelong Yan, Li Zhuang, Boyi Gan.
      Transmembrane receptor proteins are proficient in sensing external signals and initiating downstream pathways to control cell survival. Lin et al. demonstrated that GPR56, a G-protein-coupled receptor, can be activated by its agonist to suppress ferroptosis-a form of cell death-and effectively mitigate ferroptosis-associated liver damage.
    DOI:  https://doi.org/10.1016/j.cmet.2024.08.011
  6. J Lipid Res. 2024 Oct 25. pii: S0022-2275(24)00182-2. [Epub ahead of print] 100677
    Quantifying acyl-chain diversity in isobaric compound lipids containing monomethyl branched-chain fatty acids.
    C R Green, M J Kolar, G H McGregor, A T Nelson, M Wallace, C M Metallo.
      Compound lipids comprise a diverse group of metabolites present in living systems, and metabolic- and environmentally-driven structural distinctions across this family is increasingly linked to biological function. However, methods for deconvoluting these often isobaric lipid species are lacking or require specialized instrumentation. Notably, acyl-chain diversity within cells may be influenced by nutritional states, metabolic dysregulation, or genetic alterations. Therefore, a reliable, validated method of quantifying structurally similar even-, odd-, and branched-chain acyl groups within intact compound lipids will be invaluable for gaining molecular insights into their biological functions. Here we demonstrate the chromatographic resolution of isobaric lipids containing distinct combinations of straight-chain and branched-chain acyl groups via ultra-high-pressure liquid chromatography (UHPLC)-mass spectrometry (MS) using a C30 liquid chromatography column. Using metabolically-engineered adipocytes lacking branched-keto acid dehydrogenase A (Bckdha), we validate this approach through a combination of fatty acid supplementation and metabolic tracing using monomethyl branched-chain fatty acids and valine. We observe resolution of numerous isobaric triacylglycerols and other compound lipids, demonstrating the resolving utility of this method. This approach adds to the toolbox for laboratories to quantify and characterize acyl chain diversity across the lipidome.
    Keywords:  BCKDH; Branched-chain fatty acids; C30 chromatography; stable isotope tracing
    DOI:  https://doi.org/10.1016/j.jlr.2024.100677
  7. Nat Commun. 2024 Nov 04. 15(1): 9522
    PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity.
    Eduardo H Gilglioni, Ao Li, Wadsen St-Pierre-Wijckmans, Tzu-Keng Shen, Israel Pérez-Chávez, Garnik Hovhannisyan, Michela Lisjak, Javier Negueruela, Valerie Vandenbempt, Julia Bauzá-Martinez, Jose M Herranz, Daria Ezeriņa, Stéphane Demine, Zheng Feng, Thibaut Vignane, Lukas Otero Sanchez, Flavia Lambertucci, Alena Prašnická, Jacques Devière, David C Hay, Jose A Encinar, Sumeet Pal Singh, Joris Messens, Milos R Filipovic, Hayley J Sharpe, Eric Trépo, Wei Wu, Esteban N Gurzov.
      Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and correlates positively with PPARγ-induced lipogenic signaling. High-fat-fed PTPRK knockout male and female mice have lower weight gain and reduced hepatic fat accumulation. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified fructose-1,6-bisphosphatase 1 and glycolysis as PTPRK targets in metabolic reprogramming. Mechanistically, PTPRK-induced glycolysis enhances PPARγ and lipogenesis in hepatocytes. Silencing PTPRK in liver cancer cell lines reduces colony-forming capacity and high-fat-fed PTPRK knockout mice exposed to a hepatic carcinogen develop smaller tumours. Our study defines the role of PTPRK in the regulation of hepatic glycolysis, lipid metabolism, and tumour development in obesity.
    DOI:  https://doi.org/10.1038/s41467-024-53733-0
  8. Nat Commun. 2024 Nov 02. 15(1): 9475
    CLSTN3B promotes lipid droplet maturation and lipid storage in mouse adipocytes.
    Chuanhai Zhang, Mengchen Ye, Kamran Melikov, Dengbao Yang, Goncalo Dias do Vale, Jeffrey McDonald, Kaitlyn Eckert, Mei-Jung Lin, Xing Zeng.
      Interorganelle contacts facilitate material exchanges and sustain the structural and functional integrity of organelles. Lipid droplets (LDs) of adipocytes are responsible for energy storage and mobilization responding to body needs. LD biogenesis defects compromise the lipid-storing capacity of adipocytes, resulting in ectopic lipid deposition and metabolic disorders, yet how the uniquely large LDs in adipocytes attain structural and functional maturation is incompletely understood. Here we show that the mammalian adipocyte-specific protein CLSTN3B is crucial for adipocyte LD maturation. CLSTN3B employs an arginine-rich segment to promote extensive contact and hemifusion-like structure formation between the endoplasmic reticulum (ER) and LD, allowing ER-to-LD phospholipid diffusion during LD expansion. CLSTN3B ablation results in reduced LD surface phospholipid density, increased turnover of LD-surface proteins, and impaired LD functions. Our results establish the central role of CLSTN3B in the adipocyte-specific LD maturation pathway that enhances lipid storage and maintenance of metabolic health under caloric overload in mice of both sexes.
    DOI:  https://doi.org/10.1038/s41467-024-53750-z
  9. Nat Commun. 2024 Nov 06. 15(1): 9575
    Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade.
    Mayra Cruz Tleugabulova, Sandra P Melo, Aaron Wong, Alexander Arlantico, Meizi Liu, Joshua D Webster, Julia Lau, Antonie Lechner, Basak Corak, Jonathan J Hodgins, Venkata S Garlapati, Marco De Simone, Ben Korin, Shimrit Avraham, Jessica Lund, Surinder Jeet, Alexander Reiss, Hannah Bender, Cary D Austin, Spyros Darmanis, Zora Modrusan, Hans Brightbill, Steffen Durinck, Michael S Diamond, Christoph Schneider, Andrey S Shaw, Maximilian Nitschké.
      Macrophages are pleiotropic and diverse cells that populate all tissues of the body. Besides tissue-specific resident macrophages such as alveolar macrophages, Kupffer cells, and microglia, multiple organs harbor at least two subtypes of other resident macrophages at steady state. During certain circumstances, like tissue insult, additional subtypes of macrophages are recruited to the tissue from the monocyte pool. Previously, a recruited macrophage population marked by expression of Spp1, Cd9, Gpnmb, Fabp5, and Trem2, has been described in several models of organ injury and cancer, and has been linked to fibrosis in mice and humans. Here, we show that Notch2 blockade, given systemically or locally, leads to an increase in this putative pro-fibrotic macrophage in the lung and that this macrophage state can only be adopted by monocytically derived cells and not resident alveolar macrophages. Using a bleomycin and COVID-19 model of lung injury and fibrosis, we find that the expansion of these macrophages before lung injury does not promote fibrosis but rather appears to ameliorate it. This suggests that these damage-associated macrophages are not, by themselves, drivers of fibrosis in the lung.
    DOI:  https://doi.org/10.1038/s41467-024-53700-9
  10. STAR Protoc. 2024 Nov 02. pii: S2666-1667(24)00586-0. [Epub ahead of print]5(4): 103421
    Protocol for studying macrophage lipid crosstalk with murine tumor cells.
    Daan J Kloosterman, Martina Farber, Menno Boon, Johanna Erbani, Leila Akkari.
      Lipid accumulation has recently emerged as a key feature underlying the pro-tumorigenic role of macrophages. Here, we present a workflow to study macrophage lipid crosstalk with tumor cells. We describe steps for the identification, purification, and multi-omics characterization of lipid-laden macrophages (LLMs) from murine tumors and outline protocols to assess the functional significance of LLMs in cancer malignancy. This approach has the potential to uncover the source of lipids that drives LLM formation and its pro-tumorigenic potential in multiple cancer types. For complete details on the use and execution of this protocol, please refer to Kloosterman, Erbani, et al.1.
    Keywords:  RNA-seq; bioinformatics; cancer; cell biology; flow cytometry; genomics; immunology; microbiology; sequence analysis; single cell
    DOI:  https://doi.org/10.1016/j.xpro.2024.103421
  11. J Leukoc Biol. 2024 Nov 06. pii: qiae243. [Epub ahead of print]
    Glutamine modulates neutrophil recruitment and effector functions during sterile inflammation.
    Katharina E M Hellenthal, Katharina Thomas, Nadine Ludwig, Anika Cappenberg, Lena Schemmelmann, Tobias Tekath, Andreas Margraf, Sina Mersmann, Katharina Henke, Jan Rossaint, Alexander Zarbock, Wida Amini.
      During sterile inflammation, tissue damage induces excessive activation and infiltration of neutrophils into tissues, where they critically contribute to organ dysfunction. Tight regulation of neutrophil migration and their effector functions is crucial to prevent overshooting immune responses. Neutrophils utilize more glutamine, the most abundant free α-amino acid in the human blood, than other leukocytes. However, under inflammatory conditions, the body's requirements exceed its ability to produce sufficient amounts of glutamine. This study investigates the impact of glutamine on neutrophil recruitment and their key effector functions. Glutamine treatment effectively reduced neutrophil activation by modulating β2-integrin activity and chemotaxis in vitro. In a murine in vivo model of sterile inflammation induced by renal ischemia-reperfusion injury, glutamine administration significantly attenuated neutrophil recruitment into injured kidneys. Transcriptomic analysis revealed, glutamine induces transcriptomic reprogramming in murine neutrophils, thus improving mitochondrial functionality and glutathione metabolism. Further, glutamine influenced key neutrophil effector functions, leading to decreased production of reactive oxygen species and formation of neutrophil extracellular traps. Mechanistically, we used a transglutaminase 2 inhibitor to identify transglutaminase 2 as a downstream mediator of glutamine effects on neutrophils. In conclusion, our findings suggest that glutamine diminishes activation and recruitment of neutrophils and thus identify glutamine as a potent means to curb overshooting neutrophil responses during sterile inflammation.
    Keywords:  NET formation; ROS production; glutamine; neutrophil recruitment
    DOI:  https://doi.org/10.1093/jleuko/qiae243
  12. Cancer Res. 2024 Nov 04.
    PHGDH Induction by MAPK is Essential for Melanoma Formation and Creates an Actionable Metabolic Vulnerability.
    Neel Jasani, Xiaonan Xu, Benjamin Posorske, Yumi Kim, Kaizhen Wang, Olga Vera, Kenneth Y Tsai, Gina M DeNicola, Florian A Karreth.
      Overexpression of PHGDH, the rate-limiting enzyme in the serine synthesis pathway, promotes melanomagenesis, melanoma cell proliferation, and survival of metastases in serine-low environments such as the brain. Here, we found that PHGDH is universally increased in melanoma cells and required for melanomagenesis. While PHGDH amplification explained PHGDH overexpression in a subset of melanomas, oncogenic BRAFV600E also promoted PHGDH transcription through mTORC1-mediated translation of ATF4. Importantly, depletion of PHGDH in genetic mouse melanoma models blocked tumor formation. In addition to BRAFV600E-mediated upregulation, PHGDH was further induced by exogenous serine restriction. Surprisingly, BRAFV600E inhibition diminished serine restriction-mediated PHGDH expression by preventing ATF4 induction. Consequently, melanoma cells could be specifically starved of serine by combining BRAFV600E inhibition with exogenous serine restriction, which promoted cell death in vitro and attenuated melanoma growth in vivo. In summary, this study identified that PHGDH is essential for melanomagenesis and regulated by BRAFV600E, revealing a targetable vulnerability in BRAFV600E-mutant melanoma.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2471
  13. Cell Rep. 2024 Nov 05. pii: S2211-1247(24)01264-6. [Epub ahead of print]43(11): 114913
    Metabolite signatures of chronological age, aging, survival, and longevity.
    Paola Sebastiani, Stefano Monti, Michael S Lustgarten, Zeyuan Song, Dylan Ellis, Qu Tian, Michaela Schwaiger-Haber, Ethan Stancliffe, Anastasia Leshchyk, Meghan I Short, Andres V Ardisson Korat, Anastasia Gurinovich, Tanya Karagiannis, Mengze Li, Hannah J Lords, Qingyan Xiang, Megan M Marron, Harold Bae, Mary F Feitosa, Mary K Wojczynski, Jeffrey R O'Connell, May E Montasser, Nicole Schupf, Konstantin Arbeev, Anatoliy Yashin, Nicholas Schork, Kaare Christensen, Stacy L Andersen, Luigi Ferrucci, Noa Rappaport, Thomas T Perls, Gary J Patti.
      Metabolites that mark aging are not fully known. We analyze 408 plasma metabolites in Long Life Family Study participants to characterize markers of age, aging, extreme longevity, and mortality. We identify 308 metabolites associated with age, 258 metabolites that change over time, 230 metabolites associated with extreme longevity, and 152 metabolites associated with mortality risk. We replicate many associations in independent studies. By summarizing the results into 19 signatures, we differentiate between metabolites that may mark aging-associated compensatory mechanisms from metabolites that mark cumulative damage of aging and from metabolites that characterize extreme longevity. We generate and validate a metabolomic clock that predicts biological age. Network analysis of the age-associated metabolites reveals a critical role of essential fatty acids to connect lipids with other metabolic processes. These results characterize many metabolites involved in aging and point to nutrition as a source of intervention for healthy aging therapeutics.
    Keywords:  CP: Metabolism; aging; centenarians; longevity; metabolomics
    DOI:  https://doi.org/10.1016/j.celrep.2024.114913
  14. Transl Res. 2024 Oct 28. pii: S1931-5244(24)00175-0. [Epub ahead of print]275 1-17
    Blockade of TREM2 ameliorates pulmonary inflammation and fibrosis by modulating sphingolipid metabolism.
    Xueqing Gu, Hanyujie Kang, Siyu Cao, Zhaohui Tong, Nan Song.
      Pulmonary fibrosis is a chronic interstitial lung disease involving systemic inflammation and abnormal collagen deposition. Dysregulations in lipid metabolism, such as macrophage-dependent lipid catabolism, have been recognized as critical factors for the development of pulmonary fibrosis. However, little is known about the signaling pathways involved and the key regulators. Here we found that triggering receptor expressed on myeloid cells 2 (TREM2) plays a pivotal role in regulating the lipid handling capacities of pulmonary macrophages and triggering fibrosis. By integrating analysis of single-cell and bulk RNA sequencing data from patients and mice with pulmonary fibrosis, we revealed that pulmonary macrophages consist of heterogeneous populations with distinct pro-fibrotic properties, and found that both sphingolipid metabolism and the expression of chemotaxis-related genes are elevated in fibrotic lungs. TREM2, a sensor recognizing multiple lipid species, is specifically upregulated in a subset of monocyte-derived macrophages. Blockade of TREM2 by conventional/conditional knock-out or soluble TREM2 administration can attenuate bleomycin-induced pulmonary fibrosis. By utilizing scRNA Seq and lipidomics, we found that Trem2 deficiency downregulates the synthesis of various sphingomyelins, and inhibits the expression of chemokines such as Ccl2. Together, our findings not only reveal the alterations in lipidomic profiles and the atlas of pulmonary macrophages during pulmonary fibrosis, but also suggest that targeting TREM2, the crucial regulator affecting both pulmonary sphingolipid metabolism and the chemokines secretion, can benefit pulmonary fibrosis patients in the future.
    Keywords:  CCL2; Macrophage; Pulmonary fibrosis; Sphingolipid metabolism; TREM2
    DOI:  https://doi.org/10.1016/j.trsl.2024.10.002
  15. Glia. 2024 Nov 03.
    Neuroprotective effect of neuron-specific deletion of the C16 ceramide synthetic enzymes in an animal model of multiple sclerosis.
    Mario Amatruda, Damien Marechal, Mar Gacias, Maureen Wentling, Sarah Turpin-Nolan, Johannes Morstein, Mohammed Moniruzzaman, Jens C Brüning, Norman J Haughey, Dirk H Trauner, Patrizia Casaccia.
      Ceramide C16 is a sphingolipid detected at high levels in several neurodegenerative disorders, including multiple sclerosis (MS). It can be generated de novo or from the hydrolysis of other sphingolipids, such as sphingomyelin or through the recycling of sphingosine, in what is known as the salvage pathway. While the myelin damage occurring in MS suggests the importance of the hydrolytic and salvage pathways, the growing interest on the importance of diet in demyelinating disorders, prompted us to investigate the involvement of de novo ceramide C16 synthesis on disease severity. A diet rich in saturated fats such as palmitic acid, as found in many highly processed foods, provides substrates for the ceramide C16 synthetic enzymes ceramide synthase 6 (CERS6) and 5 (CERS5), which are expressed in the central nervous system. Using the experimental autoimmune encephalomyelitis (EAE) model of inflammatory demyelination, we show here that mice with CamK2a+ neuronal specific deletion of both CerS6 and CerS5 show a milder course of EAE than wild type mice, even when fed a diet enriched in palmitic acid. At a cellular level, neurons lacking both CerS6 and CerS5 are protected from the mitochondrial dysfunction arising from exposure to oxidative stress and palmitic acid in the medium. These data underscore the importance of a healthy diet avoiding processed foods for demyelinating disorders and identifies endogenous neuronal synthesis of ceramide C16 as an important determinant of disease severity.
    Keywords:  diet; experimental autoimmune encephalomyelitis; mitochondria; neurodegeneration; palm‐oil
    DOI:  https://doi.org/10.1002/glia.24631
  16. Cell Calcium. 2024 Oct 23. pii: S0143-4160(24)00120-9. [Epub ahead of print]124 102962
    Does a transmembrane sodium gradient control membrane potential in mammalian mitochondria?
    David G Nicholls.
      In a recent publication, Hernansanz-Agusti̒n et al. propose that a sodium gradient across the inner mitochondrial membrane, generated by a Na+/H+ activity integral to Complex I can account for half of the mitochondrial membrane potential. This conflicts with conventional electrophysiological and chemiosmotic understanding.
    Keywords:  Calcium signaling; Goldman equation; Membrane potential; Mitochondria; Sodium proton exchange
    DOI:  https://doi.org/10.1016/j.ceca.2024.102962
  17. Redox Biol. 2024 Oct 24. pii: S2213-2317(24)00388-4. [Epub ahead of print]78 103410
    The dithiol mechanism of class I glutaredoxins promotes specificity for glutathione as a reducing agent.
    Lukas Lang, Philipp Reinert, Cedric Diaz, Marcel Deponte.
      Class I glutaredoxins reversibly reduce glutathione- and nonglutathione disulfides with the help of reduced glutathione (GSH) using either a monothiol mechanism or a dithiol mechanism. The monothiol mechanism exclusively involves a single glutathionylated active-site cysteinyl residue, whereas the dithiol mechanism requires the additional formation of an intramolecular disulfide bond between the active-site cysteinyl residue and a resolving cysteinyl residue. While the oxidation of glutaredoxins by glutathione disulfide substrates has been extensively characterized, the enzyme-substrate interactions for the reduction of S-glutathionylated glutaredoxins or intramolecular glutaredoxin disulfides are still poorly characterized. Here we compared the thiol-specificity for the reduction of S-glutathionylated glutaredoxins and the intramolecular glutaredoxin disulfide. We show that S-glutathionylated glutaredoxins rapidly react with a plethora of thiols and that the 2nd glutathione-interaction site of class I glutaredoxins lacks specificity for GSH as a reducing agent. In contrast, the slower reduction of the partially strained intramolecular glutaredoxin disulfide involves specific interactions with both carboxylate groups of GSH at the 1st glutathione-interaction site. Thus, the dithiol mechanism of class I glutaredoxins promotes specificity for GSH as a reducing agent, which might explain the prevalence of dithiol glutaredoxins in pro- and eukaryotes.
    Keywords:  Disulfide; Dithiol; Enzyme mechanism; Glutaredoxin; Glutathione; Redox catalysis; Stopped-flow kinetics
    DOI:  https://doi.org/10.1016/j.redox.2024.103410
  18. J Leukoc Biol. 2024 Nov 04. pii: qiae242. [Epub ahead of print]
    Piezo1 restrains proinflammatory response but is essential in T cell-mediated immunopathology.
    Sung Hee Choi, Alicia Santin, Jay T Myers, Byung-Gyu Kim, Saada Eid, Suzanne L Tomchuck, Daniel T Kingsley, Alex Y Huang.
      Piezo1 is a mechanosensitive, nonselective Ca2+ channel which is broadly expressed in CD4+ T cells. Using lineage-specific Piezo1 knockout mice (Piezo1cKO), we show that loss of Piezo1 in CD4+ T cells significantly increased IFNγ and IL-17 production in vitro under TH1 and TH17 polarizing conditions, respectively. Despite their intrinsic proinflammatory phenotype, Piezo1cKO T cells are incapable of establishing disease in vivo in three separate adoptive transfer (AT) T cell-mediated inflammatory mouse models, including experimental autoimmune encephalomyelitis, inflammatory bowel disease (IBD), and graft versus-host disease. These phenomena coincided with a decreased effector memory (CD44hiCD62Llo) CD4+ T cell pool derived from donor Piezo1cKO T cells, an observation that is related to intrinsic T-cell fitness, as co-transfer IBD mouse model revealed a deficiency in the CD4+ effector memory population derived only from the naïve Piezo1cKO but not co-infused Piezo1WT CD4+ T cell source. Taken together, our results support Piezo1 as restraining proinflammatory T cell differentiation while contributing to the generation and persistence of the effector memory pool during CD4+ T cell-mediated immunopathology.
    Keywords:  CD4+ T cell; EAE; GvHD; Piezo1; T cell persistence; colitis; functional polarization; mechanosensation
    DOI:  https://doi.org/10.1093/jleuko/qiae242
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